Exceptional Responders Initiative Moving Forward

Researchers who study exceptional responders—patients who have dramatic and long-lasting responses to treatments for cancer that were not effective for most similar patients—met recently to exchange ideas and discuss the state of the science in this emerging field.

The NCI-sponsored meeting, held May 11 at NCI’s Shady Grove campus in Rockville, Maryland, featured updates on the Exceptional Responders Initiative, a pilot study that aims to gain insights into the biological mechanisms that give rise to these unusual responses to treatments.

By analyzing tumors from exceptional responders, the researchers hope to identify the genetic and molecular changes that underlie their responses to treatment. Such studies could also reveal biomarkers that could be used to predict responses to the same or similar treatments in other patients.

“The goal of the meeting was to get feedback from the community about their research on exceptional responders and to provide them updates on what NCI is doing in this area,” said Lyndsay Harris, M.D., of NCI’s Cancer Diagnosis Program, which organized the workshop.

The Exceptional Responders pilot study aims to include 100 patients with confirmed exceptional responses to treatment. More than 40 cases have been analyzed to date, Barbara Conley, M.D., of NCI’s Division of Cancer Treatment and Diagnosis said at the meeting.

“We’ve shown that it’s feasible to find exceptional responders, to enroll them on the pilot study, and to do the molecular studies,” said Dr. Harris, noting that patients enrolled on the study have a range of types of cancer, including both common tumors and rare ones.

She added: “There’s evidence from our early findings that we may be able to identify features that cause an exceptional response, but it’s going to take time.”

Investigating Exceptional Responses

Who is an Exceptional Responder?

An exceptional responder is defined as a patient with cancer who has:

a complete response to a drug(s) where complete response is seen in less than 10% of patients receiving similar treatment; or

a partial response lasting at least 6 months where such a response is seen in less than 10% of patients receiving similar treatment; or

a complete or partial response that lasts longer than 3 times the median response duration in the literature for the treatment

“This was an important meeting, and the early data from the study are promising,” said David Solit, M.D., of Memorial Sloan Kettering Cancer Center, who presented at the workshop. Dr. Solit led a 2012 study of exceptional responders that was the basis for the NCI initiative.

Since then, Dr. Solit and his colleagues have studied other exceptional responders and, in some cases, have identified molecular changes in tumor samples that may help explain why a treatment was so effective for a given patient.

One such patient was a 51-year-old woman with bladder cancer who had a complete response to a combination of two therapies during a phase I clinical trial. Genetic studies indicated that the patient had a disease-related mutation in a gene called RAD50. This mutation, the researchers reported, not only promoted the development of cancer but also made the tumor susceptible to treatment.

Until this report, the RAD50 mutation had not been viewed as a potential predictive biomarker, Dr. Solit noted. But the discovery, he suggested, could ultimately lead to therapeutic strategies for any patient with the RAD50 mutation, regardless of where the tumor occurs in the body.

Profiling Tumors

In the NCI study, patient samples are analyzed by investigators at the Baylor College of Medicine Human Genome Sequencing Center and the cancer genomics company Foundation Medicine. This process includes sequencing DNA and RNA, as well as assessing the number of copies of certain DNA segments.

“This kind of analysis helps us to look at the totality of the abnormal biology of the cell that may have contributed to the exceptional response,” said Louis Staudt, M.D., Ph.D., director of NCI’s Center for Cancer Genomics, at the workshop.

Along with each patient’s treatment records, the molecular and genetic results are reviewed by a team that includes clinicians, molecular biologists, and genomic experts, who look for clues to explain exceptional responses.

“The process can be quite laborious,” noted Dr. Harris.

The researchers will make the data available to the community through the Genomic Data Commons, which will allow other investigators to use the information to look for insights and develop hypotheses of their own.

Seeing Early Results

As an example of how studying exceptional responders can yield new insights, Dr. Staudt described a patient with metastatic breast cancer who had a complete response to docetaxel, carboplatin, and trastuzumab (Herceptin®), a combination that has not yielded prolonged responses in most other comparable patients. The complete response in this patient has lasted for 84 months.

When the researchers analyzed the patient’s tumors, they found alterations in genes that help repair damaged DNA. “This woman had a perfect storm of DNA repair mutations,” said Dr. Staudt, noting that no one had reported that combination of alterations previously.

Dr. Staudt also reported that there is preliminary evidence suggesting that the immune system might play a role in some patients’ unusual responses.

Based on their early results, the researchers estimate that between 10% and 20% of tumors from exceptional responder cases have unusually high numbers of genetic mutations. Recent studies have suggested that having an abundance of mutations may make the tumors susceptible to immune attack. There is also evidence that immune cells may infiltrate these tumors more effectively than other tumors, Dr. Staudt noted.

“The exceptional response may have to do with the immune system kicking in,” said Dr. Staudt. “I’m wondering whether this idea will be helpful, in general, in thinking about which patients might have exceptional responses to therapy.”

But it’s too early to draw firm conclusions from these early studies, Dr. Staudt cautioned. “This is a signal-finding exercise, and it’s going to require lots of work to follow up.” The pilot study will likely have results to share with the community in 2018, Dr. Harris predicted.

“We plan to have this meeting again next year,” she said. “We will be able to update the community on the information we have then.”